CMV infection of hematopoietic cell transplant (HCT) recipients is a continuing problem that impacts the[unreadable] outcome of this very successful therapy. Anti-viral treatment with ganciclovir/foscarnet is the main treatment[unreadable] strategy to prevent CMV disease post-transplant (Tx). Despite significant advances in formulation and[unreadable] delivery of anti-virals, their use complicates and extends the post-Tx recovery period and risk for CMV[unreadable] disease. Considering these caveats, we are pursuing a novel therapeutic strategy that focuses on priming or[unreadable] enhancing CMV-specific T cell immunity in healthy volunteers and HCT donors. In developing this vaccine[unreadable] strategy, it is assumed that the target population will be immunocompetent, and vaccination judged[unreadable] successful if immunity to CMV in response to the vaccine is equivalent in individuals with self-limited CMV[unreadable] infection, which at first approximation represents a protective response. Towards this end in Specific Aim[unreadable] (SA1) attenuated poxviruses (MVA) will be constructed that express four CMV antigens (CMV-MVA)[unreadable] including UL32, UL44, UL83, and UL123-exon4 for stimulation of cellular immunity to CMV. MVA has[unreadable] several advantages including avirulence, low inflammatory response and pathogenicity in humans, and[unreadable] inclusion of multiple CMV antigens will ensure broad vaccine coverage for the USA. Lack of viral assembly[unreadable] in mammals, together with studies showing its safety in heavily immunosuppressed macaques, rodents, and[unreadable] in HIV-AIDS patients is evidence of its candidacy for use in HCT recipients. CMV-MVA constructed in SA1[unreadable] will be qualified as immunologically functional, and subsequently transferred to a certified cGMP[unreadable] manufacturer for clinical production. To ensure safety of the rMVA for Tx recipients, a safety study in SA2[unreadable] will be conducted in healthy CMV positive and negative volunteers. The immunization regimen will model[unreadable] the time frame required for providing two doses of vaccine to Tx donors without delaying Tx. A Phase II trial[unreadable] using a randomized balanced cohort of 140 vaccinees and unvaccinated controls is proposed in SA3 to[unreadable] establish whether immunization of a donor with CMV-MVA prior to Tx will result in modification of the course[unreadable] and magnitude of CMV-viremia in a Tx recipient. This trial will be sufficiently powered that a 62% reduction[unreadable] in viremia will be statistically meaningful as a measure of the success of the vaccine. Successful limitation of[unreadable] acute CMV infection by this approach lays the foundation for addressing the important problem of late CMV[unreadable] disease by immunizing Tx recipients with the same or an improved version of CMV-MVA.